MD and coarse-grained modeling of TPM1. (A) Average structures for p.E192K TPM1 compared with WT TPM1 demonstrated no overt structural defects. (B) While both WT and p.E192K experienced significant residue by residue variations in flexibility as expected in this α-helical coiled coil, p.E192K was much more flexible on average. (C) A novel 2-D coarse-grained model in which a series of torsional springs assigned with the relative stiffnesses of the TPM1 residues could be deformed by an end load to result in a particular azimuthal displacement, similar to the azimuthal displacements of the TPM1 molecule across the surface actin during thin filament activation. (D) Simulations displacing the torsional spring chains with either WT or p.E192K stiffnesses to varying azimuthal displacements. (E) Total chain energies of WT and p.E192K as a function of azimuthal displacements, with fits overlaid to an elastic energy equation. aa, amino acids; arb., arbitrary; Tm, tropomyosin.